Structural genomics and the Protein Data Bank

Abstract

The field of Structural Genomics arose over the last 3 decades to address a large and rapidly growing divergence between microbial genomic, functional, and structural data. Several international programs took advantage of the vast genomic sequence information and evaluated the feasibility of structure determination for expanded and newly discovered protein families. As a consequence, structural genomics has developed structure-determination pipelines and applied them to a wide range of novel, uncharacterized proteins, often from “microbial dark matter,” and later to proteins from human pathogens. Advances were especially needed in protein production and rapid de novo structure solution. The experimental three-dimensional models were promptly made public, facilitating structure determination of other members of the family and helping to understand their molecular and biochemical functions. Improvements in experimental methods and databases resulted in fast progress in molecular and structural biology. The Protein Data Bank structure repository played a central role in the coordination of structural genomics efforts and the structural biology community as a whole. It facilitated development of standards and validation tools essential for maintaining high quality of deposited structural data. The field of Structural Genomics arose over the last 3 decades to address a large and rapidly growing divergence between microbial genomic, functional, and structural data. Several international programs took advantage of the vast genomic sequence information and evaluated the feasibility of structure determination for expanded and newly discovered protein families. As a consequence, structural genomics has developed structure-determination pipelines and applied them to a wide range of novel, uncharacterized proteins, often from “microbial dark matter,” and later to proteins from human pathogens. Advances were especially needed in protein production and rapid de novo structure solution. The experimental three-dimensional models were promptly made public, facilitating structure determination of other members of the family and helping to understand their molecular and biochemical functions. Improvements in experimental methods and databases resulted in fast progress in molecular and structural biology. The Protein Data Bank structure repository played a central role in the coordination of structural genomics efforts and the structural biology community as a whole. It facilitated development of standards and validation tools essential for maintaining high quality of deposited structural data. The concept of Structural Genomics (SG) was born as a result of exponential progress in genome sequencing. The fast growth of DNA sequence information in the 1990s led to the generation of huge amounts of genomic data, which was accompanied by significant knowledge gaps in our understanding of biological roles and biochemical functions encoded in the genomes. Of importance, the sequence information bore little insights about the proteins (often called hypothetical) these newly discovered genes programmed, hampering progress toward functional interpretation. Massive accumulation of genomic and metagenomic sequences posed many questions that could not simply be neglected or ignored. To address these new challenges, the National Institutes of Health, Department of Energy, RIKEN, Gates Foundation, Wellcome Trust, and other numerous government and private agencies around the world funded structural genomics programs as early as 1997 to 2000. Table 1 summarizes the contribution of larger SG programs to determination of protein structures.Table 1Top 20 structural genomics programsCenterNumber of PDB depositsOrigin and fundingTechniques usedRIKEN Structural Genomics/Proteomics Initiative2746Japan, government, National Project on Protein Structural and Functional AnalysesNMR, X-rayMidwest Center for Structural Genomics1955USA, PSI/NIH/NIGMSX-ray, NMRStructural Genomics Consortium1896International/a public–private partnershipX-ray, NMRJoint Center for Structural Genomics1601USA, PSI/NIH/NIGMSX-ray, NMRCenter for Structural Genomics of Infectious Diseases1359USA, NIH/NIAIDX-ray, NMR, cryo-EMSeattle Structural Genomics Center for Infectious Disease1355USA, NIH/NIAIDX-ray, NMR, cryo-EMNortheast Structural Genomics Consortium1234USA, PSI/NIH/NIGMSX-ray, NMRNew York SGX Research Center for Structural Genomics1041USA, PSI/NIH/NIGMSX-ray, NMRNew York Structural Genomics Research Consortium364USA, PSI/NIH/NIGMSX-ray, NMRTB Structural Genomics Consortium344International worldwide consortium/VariousX-ray, NMRCenter for Eukaryotic Structural Genomics219USA, PSI/NIH/NIGMSX-ray, NMRMontreal-Kingston Bacterial Structural Genomics Initiative132Canada, Canadian Institutes of Health ResearchX-ray, NMRSoutheast Collaboratory for Structural Genomics122USA, PSI/NIH/NIGMSX-ray, NMRStructural Proteomics in Europe118European UnionX-ray, NMRBerkeley Structural Genomics Center101USA, PSI/NIH/NIGMSX-rayEnzyme Discovery for Natural Product Biosynthesis91USA, NIHX-rayStructural Genomics of Pathogenic Protozoa Consortium73USA, PSI/NIH/NIGMSX-ray, NMRNew York Consortium on Membrane Protein Structure70USA, PSI/NIH/NIGMSX-rayStructure 2 Function Project54USA, PSI/NIH/NIGMSX-ray, NMRGPCR Network52USA, PSI/NIH/NIGMSX-rayNIAID, National Institute of Allergy and Infectious Diseases; NIGMS, National Institute of General Medical Sciences; NIH, National Institutes of Health; PSI, Protein Structure Initiative. Open table in a new tab NIAID, National Institute of Allergy and Infectious Diseases; NIGMS, National Institute of General Medical Sciences; NIH, National Institutes of Health; PSI, Protein Structure Initiative. The mission of SG programs was to facilitate rapid de novo structure determination for proteins representing new protein families to provide meaningful structural coverage of the genomes (1Levitt M. Nature of the protein universe.Proc. Natl. Acad. Sci. U. S. A. 2009; 106: 11079-11084Crossref PubMed Scopus (207) Google Scholar, 2Stevens R.C. Yokoyama S. Wilson I.A. Global efforts in structural genomics.Science. 2001; 294: 89-92Crossref PubMed Scopus (172) Google Scholar, 3Tepper J. Nardi G. Sutt H. Carcinoma of the pancreas: Review of MGH experience from 1963 to 1973. Analysis of surgical failure and implications for radiation therapy.Cancer. 1976; 37: 1519-1524Crossref PubMed Google Scholar), with the presumption that eventually it would be possible to generate good-quality three-dimensional models of all proteins (4Mizianty M.J. Fan X. Yan J. Chalmers E. Woloschuk C. Joachimiak A. Kurgan L. Covering complete proteomes with X-ray structures: A current snapshot.Acta Crystallogr. D Biol. Crystallogr. 2014; 70: 2781-2793Crossref PubMed Scopus (23) Google Scholar). Such a goal could be achieved by structural characterization of representative members of protein sequence families, followed by homology modeling for the remaining proteins. Selection of protein targets for structural studies has therefore become a crucial component of this effort (5Yeats C. Dessailly B.H. Glass E.M. Fremont D.H. Orengo C.A. Target selection for structural genomics of infectious diseases.Methods Mol. 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TSTMP: Target selection for structural genomics of human transmembrane proteins.Nucleic Acids Res. 2017; 45: D325-D330Crossref PubMed Scopus (6) Google Scholar). The structural biology research was set to undergo a major transformation. There were urgent needs and significant challenges to advance technologies for preparation of thousands of proteins and for their structural and functional characterization. The SG programs quickly recognized and attacked deficiencies in protein production and structure solution methods, improved effectiveness and reproducibility of scientific experiments. As a result, in the past 25 years, a number of world-wide structural genomics programs developed high-throughput pipelines for target selection, protein production, characterization, crystallization, and de novo structure determination by synchrotron-based X-ray crystallography and NMR (11Graslund S. Nordlund P. Weigelt J. Hallberg B.M. Bray J. Gileadi O. Knapp S. Oppermann U. Arrowsmith C. Hui R. Ming J. dhe-Paganon S. et al.Structural Genomics ConsortiumChina Structural Genomics ConsortiumNortheast Structural Genomics ConsortiumProtein production and purification.Nat. Methods. 2008; 5: 135-146Crossref PubMed Scopus (597) Google Scholar, 12Makowska-Grzyska M. Kim Y. Maltseva N. Li H. Zhou M. Joachimiak G. Babnigg G. Joachimiak A. Protein production for structural genomics using E. coli expression.Methods Mol. Biol. 2014; 1140: 89-105Crossref PubMed Scopus (14) Google Scholar, 13Kim Y. Babnigg G. Jedrzejczak R. Eschenfeldt W.H. Li H. Maltseva N. Hatzos-Skintges C. Gu M. Makowska-Grzyska M. Wu R. An H. Chhor G. Joachimiak A. High-throughput protein purification and quality assessment for crystallization.Methods. 2011; 55: 12-28Crossref PubMed Scopus (102) Google Scholar, 14Minor W. Cymborowski M. Otwinowski Z. Chruszcz M. HKL-3000: The integration of data reduction and structure solution--from diffraction images to an initial model in minutes.Acta Crystallogr. D Biol. Crystallogr. 2006; 62: 859-866Crossref PubMed Scopus (1339) Google Scholar). These standardized protocols ensured reproducibility of experiments and resulted in higher data quality. The tools developed by the SG consortia that streamlined the gene-to-structure approach significantly benefitted biological and biomedical research, providing insights into novel structural and functional space (11Graslund S. Nordlund P. Weigelt J. Hallberg B.M. Bray J. Gileadi O. Knapp S. Oppermann U. Arrowsmith C. Hui R. Ming J. dhe-Paganon S. et al.Structural Genomics ConsortiumChina Structural Genomics ConsortiumNortheast Structural Genomics ConsortiumProtein production and purification.Nat. Methods. 2008; 5: 135-146Crossref PubMed Scopus (597) Google Scholar, 15Burley S.K. Joachimiak A. Montelione G.T. Wilson I.A. 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The structural genomics effort was in the National Institutes of Health funded the of the Protein Structure The PSI the were on structural genomics studies of a range of model this over protein structures were of which were as to their sequence with other proteins. the the number of funded research expanded to The goal was to methods in to a large number of proteins and development in the SG the of the to the community over protein of these were of the structures were of proteins of The PSI was called and to on the scientific of The PSI with community and applied the structure determination pipelines to a range of important biological and biomedical as and proteins. The SG and that were biology between the Center for Structural Genomics and the Natural Product resulted in PDB and N. J. Hatzos-Skintges C. M. Babnigg G. Joachimiak A. Natural of the in a Biol. PubMed Scopus Google led to important in novel, as growth and of these structures for the that functional in G. K. G. E.M. Joachimiak G. Jedrzejczak R. Babnigg G. Joachimiak A. The of a novel of the A Acids Res. 2017; 45: PubMed Scopus Google Scholar). the of the PSI were structures with the of them of these were by X-ray and the by NMR M. E. Zimmerman M.D. Minor W. The of structural genomics: The Struct. PubMed Scopus Google of a of A family in that as a in growth G. K. G. E.M. Joachimiak G. Jedrzejczak R. Babnigg G. Joachimiak A. The of a novel of the A Acids Res. 2017; 45: PubMed Scopus Google as a of structure by the Center for Structural Genomics in with biology of from human A G. K. G. E.M. Joachimiak G. Jedrzejczak R. Babnigg G. Joachimiak A. The of a novel of the A Acids Res. 2017; 45: PubMed Scopus Google to the were other structural genomics programs in and Structural Genomics Consortium Structural Proteomics Structural Proteomics in and Protein in the Structural Genomics/Proteomics and international Structural Genomics Consortium The on proteins and drug targets from the National Institute for Allergy and Infectious a structural genomics Structural Genomics for Infectious the and human pathogens. The and target from the biology These over of these structures were The of high-throughput methods the and needed to structural information about proteins to drug and to international effort that from to the of the the scientific community has over structures D. M. Cymborowski M. M. A. Z. M. M. Minor W. A for structural Sci. PubMed Scopus Google Scholar), with of them by Structural Genomics for Infectious of these structures were by X-ray crystallography Y. J. Maltseva N. C. Jedrzejczak R. M. S. V. G. K. 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